WO2006071897A2 - Traitement de la degenerescence maculaire par administration de lonidamine - Google Patents

Traitement de la degenerescence maculaire par administration de lonidamine Download PDF

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WO2006071897A2
WO2006071897A2 PCT/US2005/047145 US2005047145W WO2006071897A2 WO 2006071897 A2 WO2006071897 A2 WO 2006071897A2 US 2005047145 W US2005047145 W US 2005047145W WO 2006071897 A2 WO2006071897 A2 WO 2006071897A2
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lonidamine
administered
analog
macular degeneration
administration
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PCT/US2005/047145
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WO2006071897A3 (fr
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George Tidmarsh
Steve Ammons
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Threshold Pharmaceuticals, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • This invention relates to the treatment of macular degeneration and has application in the fields of medicine, pharmacology, medicinal chemistry, chemistry, and biology.
  • Macular degeneration affects the cells of the macula and can lead to a loss of central vision, resulting in blurred vision or even blindness. Macular degeneration diminishes the quality of life and the ability of individuals suffering from it to function independently, because central vision is required for activities such as reading, driving, and facial recognition. Macular degeneration associated with aging is known as age-related macular degeneration (AMD). There are two forms of AMD: dry (atrophic or non- exudative) and neovascular/wet (exudative). Wet AMD is associated with angiogenesis. Macular degeneration can be a hereditary disease. Certain types of macular degeneration, like wet AMD, are mediated in part by angiogenesis of retinal blood vessels.
  • AMD age-related macular degeneration
  • CNV choroidal neovascularization
  • Laser photocoagulation for example, is a procedure used to treat macular degeneration.
  • Laser photocoagulation involves cauterizing the abnormal blood vessels beneath the retina to seal and prevent them from bleeding (see, for example, Chrapek, 2004, Cesk. Slov. Oftalmol., 60(1 ):45- 53, incorporated herein by reference).
  • the treatment can also destroy surrounding healthy tissue even if it is successful in preventing the leakage from abnormal vessels. Moreover, this treatment may prevent further deterioration of vision function but cannot restore lost vision function. Only a small percentage of people suffering from macular degeneration meet the requirements for this type of laser treatment, because those with occult (hidden) or subfoveal (center of macula) leakage are usually not suitable candidates for this treatment.
  • Photodynamic laser therapy using Visudyne ® is an approved therapy in the United States for treating the symptoms of wet AMD.
  • Photodynamic therapy with Visudyne ® is a two-step process, involving injection of a light activated porphyrin photosensitizer compound followed by activation of the compound with a specific wavelength of light (see Arita et a/., Nippon Yak ⁇ rigaku Zasshi, 2004, 724(6):435-44, and US Pat. No. 5,798,349, each of which is incorporated herein by reference).
  • the compound accumulates in the blood vessels formed by CNV. Upon activation, the compound catalyzes the destruction of the cells. Repeated treatment is necessary due to the continued development of new blood vessels.
  • VEGF vascular endothelial growth factor
  • Macugen ® Pegaptanib sodium for injection, OSI, see Vinores, Curr. Opin. MoI. Ther., 2003, 5(6):673-9 and US Pat. No. 6,426,335, each of which is incorporated herein by reference
  • Lucentis ® Rosumab, Genentech, see Bayes, 2003, Methods Find. Exp. CHn. Pharmacol., 25(5):387-408, incorporated herein by reference).
  • Pegaptinib sodium and ranibizumab like the porphyrin photosensitizer, are high molecular weight compounds, and thus administration, formulation, and/or manufacture can be problematic and expensive.
  • pegaptinib sodium and ranibizumab both require repeated intravitreas injection to the eye (see, Michels et al., Klin. Monatsbl. Augenheilkd., 2005, 222(6):480-4, incorporated herein by reference).
  • the present invention meets this unmet need for new therapies for macular degeneration by providing methods and compositions for treating macular degeneration.
  • the present invention provides a method for treating an angiogenic eye disease, said method comprising administering a therapeutically effective amount of lonidamine or an analog to a patient in need of such therapy.
  • the present invention provides a method for treating macular degeneration in which angiogenesis plays a causative role, such as wet AMD, said method comprising administering a therapeutically effective amount of lonidamine to a patient in need of such therapy.
  • the therapeutically effective amount is administered in a daily dose of 5-1000 mg, which daily dose can be subdivided and the fractional dose administered twice or three times per day.
  • the daily dose is administered as a single dose once a day or this dose is administered once every two days or even less frequently.
  • the daily dose of lonidamine is administered for a period of time of at least a week, a month, 3 months, 6 months, a year, until existing CNVs are prevented from growing and/or new CNVs are not formed in a patient, or up to the rest of the patient's life.
  • the lonidamine is administered orally.
  • lonidamine is administered into the eye by an intravitreas injection, an ocular implant, an eye drop, or an eye cream.
  • lonidamine is administered in a liposomal, aqueous, or cream based formulation.
  • Figure 1 illustrates graphically the effect of lonidamine on angiogenesis in a mouse model.
  • Section I provides useful definitions
  • Section Il provides a description of macular degeneration
  • Section 2005/047145
  • Section III provides a description of the therapies provided by the invention; and Section IV illustrates the method of the invention in a mouse model and describes assays for selecting particular lonidamine analogs for use in the methods of the invention. This detailed description is organized into sections only for the convenience of the reader, and disclosure found in any section is applicable to other aspects and embodiments of the invention.
  • administering or "administration of a drug to a subject (and grammatical equivalents of this phrase) can refer both to direct administration, including self-administration, and indirect administration, including the act of prescribing a drug.
  • direct administration including self-administration
  • indirect administration including the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
  • Angiogenic eye disease refers to an eye disease mediated by, caused by, or exhibiting angiogenesis as a symptom.
  • angiogenic eye diseases include wet age-related macular degeneration, diabetic retinopathy, diabetic macular edema, and retinal vein occlusion.
  • “Lonidamine” refers to 1-(2,4-dichlorobenzyl)-1-H-indazole-3-carboxylic acid, originally investigated as a male contraceptive agent and subsequently approved in certain countries in Europe for the treatment of cancer. Recently, lonidamine was identified as an effective agent for treatment of BPH (see U.S. Pat. Appl. Pub. No. 2004/0167196 and Ditonno ⁇ t al., 2005, Rev. Urol., 7(suppl 7):S27-33, both incorporated herein by reference).
  • Lonidamine analog refers to a derivative, a prodrug, a bioisostere, or a pharmacophore of lonidamine, and also includes a prodrug of a lonidamine analog (for a discussion on bioisosterism see for example Patani et a/., 1996, Chem. Rev., 96:3147-76).
  • Lonidamine analogs useful in the methods of the present invention include, for example, those described in U.S. Pat. Appl. Pub. No. 2004/0167196; US Pat. Appl. No. 10/922,747; and PCT Appl. Nos.
  • Examples of other lonidamine analogs include, but are not limited to, tolnidamine, AF-2364, and AF-2785 (see also, Ansari et ai, 1998, Contraception, 57:271-279; and Corsi et ai, 1976, J. Med.
  • Macular degeneration refers both to age related macular degeneration (AMD) and juvenile macular degeneration, including Best's disease, Stargardt's disease, and Sorsby's disease. There are two forms of AMD: dry (atrophic or non-exudative) and neovascular/wet (exudative). Wet AMD is associated with angiogenesis.
  • Patient generally refers to a human in need of therapy for the treatment of an angiogenic eye disease.
  • Patient more broadly refers to any mammal, including non-human primates, suffering from an angiogenic eye disease, and non-human mammals used as experimental models of an angiogenic eye disease.
  • prophylactically effective amount of a compound refers to an amount of a compound that, when administered to a subject, will have an intended prophylactic effect, e.g., preventing or delaying the onset (or recurrence) of an angiogenic eye disease or symptoms, or reducing the likelihood of the onset (or recurrence) of an angiogenic eye disease or symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • Reduction of a symptom or symptoms refers to a decrease in the severity or frequency of the symptom(s) of an angiogenic eye disease, or elimination of the symptom(s) of an angiogenic eye disease.
  • a “therapeutically effective amount” of a compound refers to an amount of a compound (drug) that, when administered to a subject with wet macular degeneration or other angiogenic eye disease, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation, or elimination of one or more symptoms of wet macular degeneration or the angiogenic eye disease in the subject.
  • a “therapeutically effective amount” of a compound may be an amount that, when administered to a subject delays or slows progression of the disease (compared to expected progression in the absence of treatment). The full therapeutic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations.
  • Treating" a disease, condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results, for the patient.
  • beneficial or desired clinical results include, but are not limited to, prevention, alleviation, or amelioration of an angiogenic eye disease; diminishment of extent of an angiogenic eye disease or its symptoms; delay or slowing of an angiogenic eye disease progression; amelioration, palliation, or stabilization of the angiogenic eye disease state; and other beneficial results.
  • the macula is the central portion of the retina, constituting -5% of retinal tissue, and is responsible for the fine, detailed central vision.
  • Macular degeneration, particularly AMD, is the leading cause of blindness in people over the age of 65.
  • the National Eye Institute estimates that there are 1.6 10 PCT/US2005/04 71 4 5
  • the back of the eye is lined by a sheet of nerve cells called the retina.
  • Retinal pigment epithelial cells RPE
  • the choroid is a bed of tiny blood vessels that brings oxygen and nutrients to the eye and removes waste products, such as carbon dioxide, generated by cellular metabolism.
  • the dry form of macular degeneration can arise from a disruption of the transportation of nutrients and metabolic waste via the RPE. This disruption can result in the accumulation of yellowish debris called drusen adjacent to the RPE and reduced oxygen transport via the RPE. Under these hypoxic conditions, the RPE cells and photoreceptors cells surrounding the RPE sells are damaged and die. Nutrient delivery and oxygen transport to the retina are also reduced, causing the retina to degenerate and lose function. Depending on the size and number of drusen and the nature of damage to the photoreceptors cells, dry macular degeneration is characterized into three forms: early, intermediate, and advanced dry. Extent of vision loss in patients increases from the early to the intermediate and from the intermediate to the advanced dry form.
  • Angiogenesis is the growth of new vascular structures from pre-existing vasculature such as capillaries.
  • the endothelial cells of the vasculature are attached to the basement membrane, and during angiogenesis, the ⁇ PCT/US2005/047H5
  • Angiogenesis can be initiated by molecules such as VEGF, fibroblast growth factor (FGF), transforming growth factor- ⁇ (TGF- ⁇ ), platelet-derived growth factor (PDGF), and the molecular target of Rapamycin (mTOR).
  • FGF fibroblast growth factor
  • TGF- ⁇ transforming growth factor- ⁇
  • PDGF platelet-derived growth factor
  • mTOR molecular target of Rapamycin
  • hypoxia can affect production of VEGF and other growth factors and mediate the angiogenesis in angiogenic eye diseases, including but not limited to, diabetic retinopathy, retinal vein occlusion, and wet AMD.
  • angiogenesis initiates from the deeper choroidal layer up into the RPE, into the space between the RPE and the retina, and into the retina.
  • This type of angiogenesis known as CNV
  • CNV This type of angiogenesis
  • Bleeding from CNV can damage the retina and cause visual distortions.
  • New vessels growing into the retina can create blind spots. Once the bleeding is stopped, a scar is formed that can create a blind spot in central vision. This type of degeneration is called "wet" macular degeneration.
  • CNV CNV associated with certain forms of wet macular degeneration
  • CNV can be categorized into three major types based on its relationship to the fovea, a small depression in the retina containing cone cells where vision is most ⁇ PCT/US2005/047145
  • Extrafoveal CNV occurs between 200 and 2500 ⁇ m from the center of the foveal avascular zone.
  • Juxtafoveal CNV occurs in an area up to 199 ⁇ m from the center of the foveal avascular zone and may include CNV in the foveal avascular zone.
  • Subfoveal CNV occurs directly beneath the geometric center of the foveal avascular zone.
  • CNV can also be categorized into classic CNV and occult CNV by the patterns and locations of blood leakage.
  • Blood leakage patterns can be determined for example, by fluorescein angiography (FA, see for example, Bressler, 1998, Arch. Ophthalmol., 776(4):521-2, incorporated herein by reference).
  • FA fluorescein
  • a fluorescent dye is injected into a vein in the arm, and a camera is used to photograph the back of the eye as the dye circulates though the blood vessels. If there are circulation problems, swelling, leaking, or abnormal blood vessels in the eye, the dye can reveal them.
  • Classic CNV shows lesions having well-delineated boundaries in early angiogram "frames" (the photographs taken in angiography). These lesions are further divided into predominantly classic, in which the classic component occupies more than 50% of the entire lesion at baseline, and minimally classic, in which the classic component occupies between 0 and 50% of the entire lesion area. In later angiogram frames, FA shows progressive dye leakage and pooling in the space adjacent to retina. In occult (or hidden) CNV, the blood vessels are hidden beneath the fovea and are not readily defined by angiographic patterns. 111. Treating Macular Degeneration
  • the present invention provides a method of treating an angiogenic eye disease by administering a therapeutically effective amount of lonidamine or a lonidamine analog to a patient in need of such therapy.
  • the angiogenic eye disease is wet age-related macular degeneration.
  • a therapeutically effective amount of lonidamine is administered to treat wet age-related macular degeneration.
  • the present invention provides a method of treating dry age-related macular degeneration by administering a therapeutically effective amount of lonidamine or a lonidamine analog to a patient in need of such therapy.
  • lonidamine can be administered for treating CNV.
  • patients with CNV having occult or subfoveal leakages are administered lonidamine for treating said leakage.
  • the methods of the present invention are practiced on a human patient who is not being treated for cancer or BPH.
  • the patient is a human female.
  • Suitable methods for administering lonidamine or a lonidamine analog for treating an angiogenic eye disease such as wet age-related macular degeneration can, in accordance with the present invention, employ a variety of routes, dosage schedules, and unit dose forms. Appropriate dosage schedules, routes and dosage forms will be apparent to the ordinarily skilled 14 PCT/US2005/047145
  • the dose, schedule, and duration of administration of lonidamine employed for the treatment of a particular angiogenic eye disease and patient will depend on a variety of factors.
  • One of the factors is the nature of the disease.
  • the treatment can depend upon whether extrafoveal, juxtafoveal, or subfoveal, or predominantly classic, minimally classic, or occult macular degeneration is being treated and its severity.
  • Other factors include the age, weight, and health of the subject; the subject's medical history; co-treatments, if any; the treatment goal (e.g., therapy or prophylaxis); the mode of administration of the drug; the formulation used; the patient's response to the drug; and the like.
  • the present invention provides a method for treating an angiogenic eye disease by administering the therapeutically effective amount of lonidamine in a daily dose of 5-1000 mg.
  • the angiogenic eye disease is wet age-related macular degeneration and the therapeutically effective dose of lonidamine administered is a total daily dose in the range of about 5 mg to about 1000 mg, and more than one dose is administered.
  • the dosage form is the 150 mg unit dose form marketed under the tradename DoridaminaTM (at one time marketed by ACRAF; 150 mg po), and this dosage 15 PCT/US2005/047145
  • dosage forms are administered from once to three times daily for beneficial therapeutic effect.
  • Other dosage forms provided include, for example and not for limitation, "low dosing” (e.g., dosed in the range of 5-300 mg per day total daily dosage, 5-300 mg/day, 5-150 mg/day, 5-70 mg/day, 40-70 mg/day, 40- 65 mg/day, 20-45 mg/day, 5-10 mg/day, 50-100 mg/day, 50-200 mg/day, and 50-300 mg/day), "high dosing (e.g., total daily doses greater than 500 mg, such as doses in the range 500-1000 mg/day), and "intermediate dosing” (e.g., doses greater than 300 and less than 500 mg/day, such as doses in the range >300-400 or 400 ⁇ 500, e.g., 450 mg/day).
  • low dosing e.g., dosed in the range of 5-300 mg per day total daily dosage, 5-300 mg/day, 5-150 mg/day, 5-
  • lonidamine or a lonidamine analog is administered in accordance with the present methods at a "high dosing" for 1-5 days followed by a “low dosing” for weeks or until existing CNVs are prevented from growing and/or new CNVs are not formed in a patient.
  • the therapeutically effective dose of lonidamine is administered daily or once every other day or once a week to the patient.
  • multiple administrations of lonidamine are employed in the methods of the invention.
  • the entire daily dose may be administered once daily or the daily dose may be administered in multiple smaller doses throughout the course of a day.
  • the dose can be divided into two smaller doses and administered twice daily, or divided into three smaller doses and administered thrice daily.
  • the lonidamine or lonidamine analog need not, however, be administered daily; for example a daily dose used for some patients or indications may be, in other patients or for other indications be given every other day, or less frequently. ⁇ T/US2005/047145
  • the daily dose is repeatedly administered over a period of time.
  • the administration of the therapeutically effective daily dose is continued for multiple days, typically for at least three consecutive days, or for at least a week, or for several weeks, or for several months, or for several years, until existing CNVs are prevented from growing and/or new CNVs are not formed in a patient, or up to the rest of the patient's life.
  • treatment can be suspended temporarily if toxicity is observed or for the convenience of the patient without departing from the scope of the invention.
  • lonidamine is administered qd, bid, tid, qid, qod, or qweek, and treatment is continued for a period ranging from three days to the longer periods enumerated above. In one embodiment, treatment is continued for one to three months. In another embodiment, the treatment is continued for a year.
  • lonidamine or a lonidamine analog is administered a single time or many times over periods as long as several months or years. During this time period dosing may be as frequent as enumerated above and continuous for as long as two to six months or a year, or for a lesser time of one to eight weeks.
  • a dose of up to 150 mg lonidamine or a lonidamine analog administered by intravitreous injection, by eyedrops, or by oral administration qod, qd, or tid for 7-30 days can provide therapeutic or prophylactic benefit for an extended period of time (3 months or longer, including up to 6 months and one year), while limiting or eliminating any unwanted side effects.
  • an angiogenic eye disease or one or more of its symptoms are treated in 17 PCT/US2005/047145
  • lonidamine or a Ionidamine analog in one embodiment, a single administration of lonidamine or a lonidamine analog in the range of 100-1000 mg is sufficient to provide protection for a period of one week or several months.
  • dosing schedules are for illustration and not limitation, and that a dosing schedule may be changed during a course of therapy based on, for example, a patient's response.
  • Guidance concerning dosing schedules can also be provided by prior experience using lonidamine for a different indication (for example, lonidamine, has been administered to treat cancer (supra), and is administered to treat BPH at a daily dose of 150 mg, for a period of about a month), and from new studies in humans and other mammals.
  • lonidamine or a lonidamine analog is administered by intravitreas injection.
  • Suitable methods for intravitreous injection of lonidamine or a lonidamine analog can be adapted from those reported for pegaptanib in the treatment of neovascular AMD (see Gragoudas et al., 2004, N. Engl. J. Med., 351 :2805-16, incorporated herein by reference), and for ranibizumab (see Michels et a/., 2005, Klin Monatsbl.
  • the therapeutically effective daily dose of lonidamine or a lonidamine analog administered daily by intravitreous injection is about 0.05 - 50 mg per eye, about 0.5 - 10 mg per eye, or about 1-5 mg per eye. In one embodiment, the therapeutically effective dose of lonidamine or a lonidamine analog is administered once every week to once every 10 weeks by intravitreous injection. In various embodiments, said administration by intravitreaous injection is continued for about 2-100, about 4-48, and about 10-20 weeks.
  • the lonidamine or lonidamine analog is administered orally. In other embodiments, the lonidamine or lonidamine analog is administered to the eye as an eye drop, an ointment, or a cream. In another embodiment, lonidamine or lonidamine analog is administered parenterally. In still other embodiments, other routes of administration are employed, including transdermal, inhalation spray, rectal, and vaginal routes of administration.
  • Formulations useful for the different modes of administration include but are not limited to aqueous formulations and liposomal formulations useful for ocular administration and certain formulations useful for oral administration and are described in more detail in the following subsection.
  • compositions are employed for administering lonidamine or a lonidamine analog in the treatment of an angiogenic eye disease in accordance with methods of the invention.
  • the formulations provided by and useful in the methods of the invention contain ⁇ T/US2005/047145
  • the present invention provides a formulation suitable for ocular administration.
  • the formulation is suitable for intravitreas injection.
  • the formulation is suitable for administration as eye drops.
  • the formulation is suitable for use as an ocular implant.
  • an aqueous formulation is administered in the method of the invention.
  • the aqueous formulation of lonidamine or a lonidamine analog includes an acid or a base addition salt of lonidamine or a lonidamine analog admixed with a pharmaceutically acceptable aqueous carrier. Suitable acid and base addition salts of lonidamine and lonidamine analogs are described for use in other methods in PCT Appl. No. PCT/US2005/027092.
  • lonidamine and lonidamine analogs are formulated as their base addition salts for administration by intravitreous or parenteral injection.
  • the base addition salt is a metal salt.
  • bases suitable for base addition salts of lonidamine and lonidamine analogs are amines; alkali metal hydroxides, carbonates, or bicarbonates; and alkaline earth metal hydroxides, carbonates, or bicarbonates.
  • the amines are primary amines, secondary amines, tertiary amines, amino acids, or naturally occurring ⁇ -amino acids. Examples of amino acids include but are not limited to glycine, lysine, and arginine.
  • lonidamine analog contains as cation a sodium, a potassium, an ammonium, or a calcium ion.
  • base addition salts of lonidamine and lonidamine analogs are formed employing lysine, glycine, or arginine as a base.
  • the base addition salt of lonidamine or the lonidamine analog is dissolved in 0.9% aqueous sodium chloride and/or 5% aqueous dextrose solution and administered according to the present methods by intravitreous injection or parenteral injection.
  • the base addition salt of lonidamine and arginine is intravenously administered to mammals other than rats.
  • the base addition salt of lonidamine and glycine is intravenously administered to mammals other than normal dogs.
  • the base when in a base addition salt one component is lonidamine, the base is other than arginine or glycine.
  • one equivalent of an amine (wherein amine is as described above) is mixed with one equivalent of lonidamine or a lonidamine analog in water and the mixture shaken or sonicated to yield a homogenous solution of the base addition salt of lonidamine or the lonidamine analog in water.
  • one equivalent of lonidamine or a lonidamine analog is mixed in water with one equivalent of a metal hydroxide, oxide, bicarbonate, or carbonate wherein the metal includes, but is not limited to, sodium, potassium, or calcium, resulting in the formation of the metal salt of lonidamine or the lonidamine analog.
  • a liposomal formulation is administered.
  • a liposomal formulation of lonidamine is employed for administration by intravitreas injection. Methods for making liposomal formulations suitable for intravitreas injection are described in US Pat. No. ⁇ US2005/047145
  • Liposomal formulations of lonidamine are described in US Pat. Nos. 6,337,087 and 6,319,517, each of which is incorporated herein by reference.
  • Liposomal formulations of lonidamine or a lonidamine analog employed in the present invention can also be made by the methods described in US Pat. Nos. 6,426,335; 6,337,087; and 6,319,517, with appropriate substitution of active pharmaceutical ingredient.
  • lonidamine is formulated for oral administration for use in the methods of the present invention.
  • suitable formulations for oral delivery include pills, tablets, capsules, caplets, and the like, optionally formulated for sustained release (see for example, Marshall, 1979, Modern Pharmaceutics, 7: 359-427 Banker et al., editors).
  • Other suitable forms for oral administration include troches, elixirs, suspensions, syrups, wafers, lozenges, and the like.
  • the present invention provides eye ointments and cream formulations containing lonidamine or a lonidamine analog for treating macular degeneration.
  • the formulation is an eye ointment that contains lonidamine or a lonidamine analog along with a paraffinic or a water miscible ointment base.
  • lonidamine or a lonidamine analog is formulated in an eye cream with an oil-in-water cream base.
  • the aqueous phase of the cream base includes, w/w, at least about 30% of a polyhydric alcohol.
  • the polyhydric alcohol is an alcohol having two or more hydroxyl groups including but not limited to propylene glycol, butane-1 ,3- diol, mannitol, sorbitol, glycerol, and polyethylene glycol and mixtures thereof. 22 PCT/US2005/047145
  • the oily phase of the cream can be constituted from known ingredients in manners known for formulations of other compounds.
  • the oily phase comprises an emulsifier or an emulgent, or a mixture of at least one emulsifier with a fat or an oil or with both.
  • the cream includes a hydrophilic emulsifier together with a lipophilic emulsifier acting as a stabilizer.
  • the cream includes both an oil and a fat.
  • Emulgents and emulsion stabilizers suitable for use in the formulations of the present invention include but are not limited to Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulphate.
  • Suitable oils or fats employed for such formulations of the invention are provided to achieve the desired solubility properties, because the solubility of lonidamine and certain lonidamine analogs in most oils used in pharmaceutical emulsion formulations is low.
  • the cream is typically a non- greasy, non-staining, and washable product, with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, ethylhexyl palmitate, or a blend of branched chain esters known as Crodamol CAP can be used. These may be used alone or in combination, depending on the properties desired. In other embodiments, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used. 23 PCT7US2005/047145
  • lonidamine is formulated for controlled and sustained release formulations that can allow less frequent dosing.
  • Such formulations can be administered by ocular implants, for example.
  • Unit dose forms of lonidamine or lonidamine analogs formulated for administration according to the method of the present invention are described below.
  • a therapeutically effective dose of lonidamine is administered by employing a suitable unit dose form of lonidamine.
  • the methods of the invention are practiced with lonidamine in the unit dose form formerly marketed as DoridaminaTM (ACRAF) in Italy (150 mg tablet for oral administration).
  • ACRAF DoridaminaTM
  • pharmaceutical formulations of unit dose forms of lonidamine or lonidamine analogs suitable for administration by intravitreas injection contain about 0.05 mg to about 50 mg, about 0.5 mg to about 50 mg, about 1 mg to about 25 mg, about 5 mg to about 10 mg of lonidamine.
  • pharmaceutical formulations of unit dose forms of lonidamine or lonidamine analogs suitable for administration orally (as tablets, capsules, and pills), by parenteral injection, or by means of an eye drop or an eye ointment contain about 5 mg to about 1000 mg, about 10 mg to about 500 mg, about 20 mg to about 250 mg, about 30 mg to about 150 mg, about 50 mg to about 100 mg, about 5 mg to about 50, about 5 to about 25 mg, and about 5 mg to about 10 mg of lonidamine.
  • a unit dose form contains 1 , 2, 5, 25, 50, 100, or 150 mg lonidamine.
  • the method of the present invention can be practiced for treating angiogenic eye diseases other than wet AMD.
  • One angiogenic eye disease, diabetic retinopathy results when capillaries in the retina undergo angiogenesis and invade a region between the eye lens and the retina called the vitreous humor, bleed, and cause blindness.
  • the present invention provides a method for treating diabetic retinopathy by administering a therapeutically effective amount of lonidamine or a lonidamine analog to a patient in need of such therapy.
  • the therapeutically effective amount of lonidamine or a lonidamine analog can prevent or inhibit angiogenesis of capillaries in the retina resulting from diabetic retinopathy.
  • lonidamine or a lonidamine analog is administered in a therapeutically effective amount for treating diabetic macular edema and retinal vein occlusion.
  • Administration of pegaptinib sodium to evaluate its usefulness in treating diabetic macular edema is reported in the reference Cunningham et al., 2005, Ophthalmology, 112(10): 1747-57.
  • a method of treating diabetic macular edema by administration of lonidamine or a lonidamine analog can be adapted from the method described in the reference Cunningham et al. (supra) substituting for pegaptinib a therapeutically effective amount of lonidamine or a lonidamine analog.
  • lonidamine or a lonidamine analog is administered in combination with another agent or procedure to a patient to treat an angiogenic eye disease, ameliorate symptoms of said disease, potentiate the effects of lonidamine or the lonidamine analog, or provide other therapeutic benefit.
  • Administration of lonidamine or a lonidamine analog "in combination” includes parallel administration (such as administration of lonidamine or a lonidamine analog and the other agent on alternate days for one month), coadministration (in which lonidamine or a lonidamine analog and the other agent are administered at approximately the same time, e.g., within about 30 minutes of each other), and co-formulation (in which lonidamine or a lonidamine analog and the other agent are combined or compounded into a single dosage form suitable for intravitreas, oral, parenteral, or other ocular administration).
  • agents or therapies for administration in combination with lonidamine or a lonidamine analog include, but are not limited to, Visudyne®, Macugen®, Lucentis®, and laser photocoagulation.
  • Other agents, procedures, and therapies that may in the future be approved for the treatment of an angiogenic eye disease can be used in combination with the administration of lonidamine or a lonidamine analog.
  • a therapeutically effective human dose can be extrapolated from a mouse dose in mg/kg by dividing by 12.3, yielding, in this model, a human dose. This approximation provides a human dose of lonidamine of ⁇ 4-33 mg/kg (or a daily dose of -280 mg-2.3 g) po qd.
  • a lonidamine analog particularly useful in the methods of the present invention can also be selected using this system and mouse model described in Example 1.
  • this system one measures the hemoglobin that accumulates in the matrigel plug injected in mice treated with the lonidamine analog and compares that measured amount with that from a control (vehicle) plug. The lower the amount of hemoglobin measured in the test system relative to the control, the more active the analog in preventing angiogenesis.
  • a lonidamine analog showing a >20% reduction of measured hemoglobin in the matrigel plug injected in mice treated with that lonidamine analog compared to the hemoglobin in a control (vehicle) plug is used in the methods of the present invention.
  • a lonidamine analog showing a reduction of measured hemoglobin in the matrigel plug injected in mice treated with that lonidamine analog that is equal to or greater than the reduction in hemoglobin in mice treated with an equal weight of lonidamine is used in the methods of the present invention.
  • this system can be used to measure angiogenesis as follows. After treatment with the test and control compounds, one excises the matrigel plug, conducts histological analysis using H&E staining, and then counter stains with antibodies for endothelial cells markers, such as anti- CD31. The higher the level of anti-CD31 staining, the higher the blood vessel density and the extent of angiogenesis in the plug. In one embodiment, a ⁇ T/US2005/047145
  • lonidamine analog showing a greater than 20% reduction in the level of anti- CD31 staining in the matrigel plug injected in mice treated with that lonidamine analog compared to the anti-CD31 staining in a control (vehicle) plug, is used in the methods of the present invention.
  • a lonidamine analog particularly useful in the methods of the present invention can also be selected using the methods described Examples 2 and 3.
  • lonidamine was not effective in reducing angiogenesis levels in the implanted matrigel in a statistically significant manner.
  • the absence of a dose dependent reduction of angiogenesis in the implanted matrigel plug demonstrated that this test system was not suitable for measuring inhibition of angiogenesis in a reliable manner.
  • the procedure was then modified such that the lonidamine was not premixed in an injected matrigel but was instead orally administered, to mice (4 groups, 10 mice/group) that had been previously injected subcutaneously in the abdomen with matrigel plugs (500 ⁇ L each) premixed with human VEGF (60 ng/plug) and heparin (20 U/plug).
  • Lonidamine exhibited a dose- dependent inhibition of angiogenesis in this model.
  • Lonidamine was administered at various doses (0 (vehicle), 50, 100, 200, and 400 mg/kg) once a day for 5 days by oral gavage. Twenty-four hours after the final treatment, the matrigel, which was rigid and vascularized, was ⁇ OO 5 ZO 47145
  • the amount of hemoglobin in the matrigel is proportional to blood vessel formation or angiogenesis in the matrigel, so the extent of angiogenesis in the matrigel can be inferred from and quantified by measuring the amount of hemoglobin in the matrigel. A dose dependent decrease in the amount of hemoglobin was observed, demonstrating the anti-angiogenic activity of lonidamine, as illustrated in Figure 1.
  • a particular lonidamine analog useful in the present methods is selected by it ability to reduce CNV related leakage in a monkey model described in US Pat. No. 6,225,303, incorporated herein by reference.
  • cynomolgus monkeys weighing 3-4 kg are anesthetized and their pupils dilated with phenylephrine and tropicamide.
  • CNV is then produced in the eyes of the monkeys by burning their macula with a laser beam (see for example, Ohkuma, et al. 1983, Arch. Ophthalmol., 707:1102-10 and Ryan, 1982, Arch. Ophthalmol., 700:1804-9, each of which is incorporated herein by reference).
  • the resulting CNVs can be observed by fluorescein angiography, fundus photography, and histological examination by light and electron microscopy.
  • Lonidamine analogs that result in reduced CNV related leakages in a statistically significant manner relative to that observed in the control group are selected for use in the methods of the present invention.
  • a particular lonidamine analog useful in the present methods is selected by its ability to reduce VEGF-induced corneal angiogenesis in the normally avascular rat cornea.
  • biopolymer Hydron pellets with and without VEGF (3 pmol) are prepared by adding the protein or carrier solution to 12% biopolymer in 95% ethanol.
  • Adult, Sprague-Dawley rats (200- 240 g) are anesthetized by intraperitoneal injection of ketamine HCI (50 mg/kg) and xylazine (10 mg/kg).
  • the left eye is then prepared by topical administration of tetracaine HCI for local anesthesia followed by application of dilute povidone-iodine solution and subsequent rinsing with isotonic saline solution.
  • a vertical partial thickness incision can be made in the mid-cornea.
  • a mid-stromal pocket can be dissected caudally toward the lateral canthus extending to within 1.5 mm of the limbus.
  • a biopolymer pellet prepared earlier is then inserted into and pushed to the caudal limit of the pocket. Residual air is gently massaged out of the pocket.
  • a drop of chloramphenicol ophthalmic solution is applied to the eye. The procedure is then repeated on the right eye with insertion of the same type of pellet.
  • each animal Upon completion of pellet insertion in each eye, each animal is then administered either a lonidamine analog or phosphate buffered saline (PBS) intravenously. At 5 days, each animal is anesthetized and photographs of the eyes are taken using a 35 mm camera (Minolta X9) mounted on a dissecting microscope (KAPS, Germany). Each eye is evaluated for angiogenesis by measuring the maximum length of vessel growth (0-5), the density of vessel 2 i T7US2005/047145
  • An angiogenic index can then be determined as the product of length X density X circumference.
  • a lonidamine analog reducing the level of VEGF-induced angiogenesis by 30-95%, 40-80%, or 65-70% over the angiogenesis in the control in this model is selected for use in a method of the present invention.

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Abstract

L'invention concerne le traitement de la dégénérescence maculaire par administration d'une dose efficace sur le plan thérapeutique de lonidamine ou d'un analogue de celle-ci.
PCT/US2005/047145 2004-12-23 2005-12-22 Traitement de la degenerescence maculaire par administration de lonidamine WO2006071897A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009138156A1 (fr) * 2008-05-15 2009-11-19 Beiersdorf Ag Préparations cosmétiques pour réduire les odeurs de transpiration à l’aide de modulateurs des abcc
US11407999B2 (en) * 2019-07-01 2022-08-09 Seoul National University R&Db Foundation Pharmaceutical composition for preventing or treating angiogenesis relating ocular diseases comprising inhibitors of MCT expression or activity

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6482802B1 (en) * 1998-05-11 2002-11-19 Endowment For Research In Human Biology, Inc. Use of neomycin for treating angiogenesis-related diseases

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6482802B1 (en) * 1998-05-11 2002-11-19 Endowment For Research In Human Biology, Inc. Use of neomycin for treating angiogenesis-related diseases

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009138156A1 (fr) * 2008-05-15 2009-11-19 Beiersdorf Ag Préparations cosmétiques pour réduire les odeurs de transpiration à l’aide de modulateurs des abcc
US11407999B2 (en) * 2019-07-01 2022-08-09 Seoul National University R&Db Foundation Pharmaceutical composition for preventing or treating angiogenesis relating ocular diseases comprising inhibitors of MCT expression or activity

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TW200633705A (en) 2006-10-01

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